Chromatin modification plays an essential role in transcriptional regulation (T. Kouzarides, 2007, Cell 128: 693-705). These modifications, which include DNA methylation, histone acetylation and hsitone methylation, are disregulated in tumors. This epigenetic disregulation plays an important role in the silencing of tumor suppressors and overexpression of oncogenes in cancer (M. Esteller, 2008, N Engl J Med 358:1148-59. P. Chi et al, 2010, Nat Rev Canc 10:457-469.). The enzymes that regulate histone methylation are the histone methyl transferases and the histone demethylases.
Lysine-specific demethylase 1 (LSD1; also known as BHC110) is a histone lysine demethylase reported to demethylate H3K4mel/2 (Y. Shi et al., 2004, Cell 119: 941-953) and H3K9mel/2 (R. Schule et al., 2005, Nature 437: 436-439). LSD1 is overexpressed in multiple human cancers, including prostate where it is associated with more frequent relapse (P. Kahl et al., 2006, Canc. Res. 66: 11341-11347), breast (J. Kirfel et al., 2010, Carcinogenesis 31: 512-520) and neuroblastoma (J. Kirfel et al., 2009, Canc. Res. 69: 2065-2071. G. Sun et al., 2010, Mol. Cell. Biol. 28: 1997-2000). LSD1 is essential for transcriptional regulation mediated by a number of nuclear hormone receptors, including androgen receptor in prostate cancer (R. Schuele et al., 2005, Nature 437: 436-439. R. Schuele et al., 2007, Nat. Cell Biol. 9: 347-353. R. Schuele et al., 2010, Nature 464: 792796), estrogen receptor in breast carcinomas (M. G. Rosenfeld et al., 2007, Cell 128: 505-25518), and TLX receptor in neuorblastoma (S. Kato et al., 2008, Mol. Cell. Biol. 28: 3995-4003). These studies have shown that knockdown of LSD1 expression results in decreased cancer cell proliferation. Additionally, LSD1 is overexpressed in multiple cancer types that are nuclear hormone receptor-independent. Those tumors include ER-negative breast (J. Kirfel et al., 2010, Carcinogenesis 31: 512-520), small-cell lung, bladder, head & neck, colon, serous ovary, and kidney Wilm's tumor.
There is a need for treatments for cancer and other diseases. There is also a need for inhibitors of LSD1 that may be useful for the treatment of various diseases (e.g., cancer)